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Transition Metal Chemistry

, Volume 44, Issue 2, pp 187–205 | Cite as

Induction of apoptosis in SGC-7901 cells by ruthenium(II) complexes through ROS-mediated lysosome–mitochondria dysfunction and inhibition of PI3K/AKT/mTOR pathways

  • Qiao-Yan Yi
  • Yang-Jie Wang
  • Miao He
  • Wen-Yao Zhang
  • Fan Du
  • Yi-Ying Gu
  • Lan Bai
  • Yun-Jun LiuEmail author
Article
  • 52 Downloads

Abstract

Five Ru(II) polypyridyl complexes [Ru(N–N)2(nfip)](ClO4)2 (N–N = dmb, 1; bpy, 2; ttbpy, 3, phen, 4, dmp, 5) were synthesized and characterized. The cytotoxic activities of the complexes against cancer SGC-7901, Eca-109, HepG2, A549, HeLa and normal LO2 cells were investigated using the MTT method. Complexes 14 show high cytotoxicity against SGC-7901 cells with low IC50 values of 12.4 ± 1.4, 6.7 ± 1.6, 1.3 ± 0.5 and 1.1 ± 0.4 µM, respectively. Complex 5 is active against HeLa cells with an IC50 value of 2.2 ± 0.6 µM. Among these complexes, complexes 3 and 4 exhibit higher cytotoxic activity than cisplatin toward SGC-7901 cells under identical conditions. Apoptosis was assayed using the AO/EB staining method and flow cytometry. The location of the complexes at lysosomes and mitochondria, the permeability of lysosomes, the levels of reactive oxygen species, and the changes of mitochondrial membrane potential were studied by fluorescence microscopy. The cell cycle distribution of SGC-7901 cells induced by the complexes was studied by flow cytometry. The expression of caspase-3, PARP and Bcl-2 family proteins was investigated by Western blot. The complexes were shown to accumulate in the lysosomes and then enter into the mitochondria. The mechanism demonstrates that the complexes induce apoptosis in SGC-7901 cells through three pathways: (1) ROS-mediated lysosomal–mitochondrial dysfunction; (2) inhibition of PI3K/AKT/mTOR pathway; and (3) DNA damage and inhibition of the cell growth at G0/G1 or S phase.

Notes

Acknowledgements

This work was supported by the National Nature Science Foundation of China (No. 21877018) and the Natural Science Foundation of Guangdong Province (No. 2016A030313728).

Supplementary material

11243_2018_283_MOESM1_ESM.docx (1 mb)
Supplementary material 1 (DOCX 1027 kb)

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.School of PharmacyGuangdong Pharmaceutical UniversityGuangzhouPeople’s Republic of China

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